Insulin-like growth factors inhibit dendritic cell-mediated anti-tumor immunity through regulating ERK1/2 phosphorylation and p38 dephosphorylation

Huang, Cheng Tung; Chang, Ming; Chen, Yuli; Chen, Tsung-Ching; Chen, Chi-An; Cheng, Wen‐Fang

doi:10.1016/j.canlet.2015.01.007

Cited by 42 publications

(35 citation statements)

References 36 publications

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“…EGFR knockout inhibited the secretion of IGF-1, which plays a key role in cell growth, differentiation, survival, transformation, and metastasis. IGF-1 is overexpressed in pancreatic, colon, breast, and ovarian cancers [40–43]. Our results also indicated that colon cancer tumor cells secrete IGF-1.…”

Section: Discussionsupporting

confidence: 65%

Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells

Zhang

Chen

et al. 2016

Oncotarget

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Epidermal growth factor receptor (EGFR) is a target of colon cancer therapy, but the effects of this therapy on the tumor microenvironment remain poorly understood. Our in vivo studies showed that cetuximab, an anti-EGFR monoclonal antibody, effectively inhibited AOM/DSS-induced, colitis-associated tumorigenesis, downregulated M2-related markers, and decreased F4/80+/CD206+ macrophage populations. Treatment with conditioned medium of colon cancer cells increased macrophage expression of the M2-related markers arginase-1 (Arg1), CCL17, CCL22, IL-10 and IL-4. By contrast, conditioned medium of EGFR knockout colon cancer cells inhibited expression of these M2-related markers and induced macrophage expression of the M1-related markers inducible nitric oxide synthase (iNOS), IL-12, TNF-α and CCR7. EGFR knockout in colon cancer cells inhibited macrophage-induced promotion of xenograft tumor growth. Moreover, colon cancer-derived insulin-like growth factor-1 (IGF-1) increased Arg1 expression, and treatment with the IGF1R inhibitor AG1024 inhibited that increase. These results suggest that inhibition of EGFR signaling in colon cancer cells modulates cytokine secretion (e.g. IGF-1) and prevents M1-to-M2 macrophage polarization, thereby inhibiting cancer cell growth.

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Section: Discussionsupporting

confidence: 65%

Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells

Zhang

Chen

et al. 2016

Oncotarget

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“…On the other hand, MycL and Irf4 , which modulate T cell priming and the induction of different helper T cell lineages by DCs192021, were expressed at higher levels in sparse cultures indicating potentially unique features of antigen presentation in the two DC types. This hypothesis was further supported by the accumulation of a diverse set of mediators involved in immunosuppressive mechanisms among the genes highly expressed in dense DC cultures222324252627282930, including Lair1 , Arg1 , Vegfa , Igf1 , Stab1 , Pf4 , Nt5e , Cd276 , Cd200 (Fig. 1g).…”

Section: Resultsmentioning

confidence: 70%

Immunogenicity is preferentially induced in sparse dendritic cell cultures

Nasi

Bollampalli

Sun

et al. 2017

Sci Rep

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We have previously shown that human monocyte-derived dendritic cells (DCs) acquired different characteristics in dense or sparse cell cultures. Sparsity promoted the development of IL-12 producing migratory DCs, whereas dense cultures increased IL-10 production. Here we analysed whether the density-dependent endogenous breaks could modulate DC-based vaccines. Using murine bone marrow-derived DC models we show that sparse cultures were essential to achieve several key functions required for immunogenic DC vaccines, including mobility to draining lymph nodes, recruitment and massive proliferation of antigen-specific CD4+ T cells, in addition to their TH1 polarization. Transcription analyses confirmed higher commitment in sparse cultures towards T cell activation, whereas DCs obtained from dense cultures up-regulated immunosuppressive pathway components and genes suggesting higher differentiation plasticity towards osteoclasts. Interestingly, we detected a striking up-regulation of fatty acid and cholesterol biosynthesis pathways in sparse cultures, suggesting an important link between DC immunogenicity and lipid homeostasis regulation.

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“…IGF-1 binds to and activates IGF-1 TK receptors (namely IGF1R and IGF2R) on tumor cells, thus activating phosphorylation cascades that converge on RAS/RAF/MEK/MAPK or RAS/PI3K/AKT/mTOR pathway signaling, thus stimulating cell proliferation and inhibiting apoptosis (69). Targeting IGF-1 signaling could affect tumor growth, while contemporarily hampering IGF-1-induced immunodepression and stimulating an effective antitumor response (79, 80). …”

Section: Metabolic Pathways That Sustain Cancer Cell Survival and Promentioning

confidence: 99%

Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions

et al. 2016

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Most tumors display oncogene-driven reprogramming of several metabolic pathways, which are crucial to sustain their growth and proliferation. In recent years, both dietary and pharmacological approaches that target deregulated tumor metabolism are beginning to be considered for clinical applications. Dietary interventions exploit the ability of nutrient-restricted conditions to exert broad biological effects, protecting normal cells, organs and systems, while sensitizing a wide variety of cancer cells to cytotoxic therapies. On the other hand, drugs targeting enzymes or metabolites of crucial metabolic pathways can be highly specific and effective, but must be matched with a responsive tumor, which might rapidly adapt. In this Review, we illustrate how dietary and pharmacological therapies differ in their effect on tumor growth, proliferation and metabolism, and discuss the available preclinical and clinical evidence in favor or against each of them. We also indicate, when appropriate, how to optimize future investigations on metabolic therapies on the basis of tumor- and patient-related characteristics.

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Insulin-like growth factors inhibit dendritic cell-mediated anti-tumor immunity through regulating ERK1/2 phosphorylation and p38 dephosphorylation

Cited by 42 publications

References 36 publications

Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells

Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells

Immunogenicity is preferentially induced in sparse dendritic cell cultures

Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions

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